While orthopedic implant fixation methods have advanced over the last several decades, failure rates of cementless total joint arthroplasties remain higher than cemented total joint arthroplasties, therefore enhancing bone integration of these implants remains a major clinical challenge. Therapies to stimulate bone formation or prevent bone resorption, such as intermittent administration of parathyroid hormone (PTH) or osteoprotegerin (OPG) treatment may benefit osseointegration to improve fixation and long-term surgical outcomes. In addition, patients resume normal activities of daily living post-operatively, so mechanical loading, a proven anabolic treatment, is ongoing and must be considered in conjunction with these pharmacologic interventions. Before these treatments can be implemented clinically, the influence that mechanical loading, PTH and OPG have on osseointegration must be investigated both at the tissue and cellular levels. The aim of this study is to better understand the role that systemically delivered anabolic or anti-catabolic agents play in the osseointegration of metallic implants in an in vivo mechanically loaded rabbit model. Our hypothesis is that mechanical loading combined with an anabolic (PTH) agent or an anti-catabolic agent (OPG) will enhance peri-implant cancellous bone volume and osseointegration of a porous metallic implant via effects on both osteoblasts and osteoblasts. Osseointegration into a metallic implant and peri-implant cancellous bone will be assessed by examining bone ingrowth and the peri- prosthetic tissue integrity using mechanical testing, backscattered scanning electron microscopy (BSE), microcomputed tomography (microCT), bone histomorphometry, immunohistochemistry and qRT-PCR. With these experiments we hope to a) demonstrate osseointegration of metallic implants can be enhanced by mechanical loading and administration of a systemic anabolic agent, PTH or a systemic anti-catabolic agent, OPG, and b) explore the cellular mechanisms triggered by these stimuli during osseointegration of metallic implants. PUBLIC HEALTH RELEVANCE: Contemporary metallic implants used in orthopaedics rely on bone ingrowth into the implant for both early and long-term fixation and ultimately clinical success. Failure of total joint implant fixation remains a clinical problem that leads to revision, individual patient morbidity and societal costs. Combining mechanical loading, an anabolic agent such as intermittent parathyroid hormone or an anti-catabolic agent such as osteoprotegerin, may enhance the ingrowth of bone into these metallic implants more rapidly and more robustly, allowing patients to return to function earlier and allow implants to last longer without loosening.